Rheumatoid arthritis (RA) is a chronic inflammatory disease that manifests predominantly as a destructive synovitis. In spite of the prominence of the synovial inflammation, many immunological abnormalities are systemic. Autoantibodies are not tissue-specific and are directed against global antigens such as Ig Fc determinants and neoantigens of citrullinated peptides. T cell abnormalities in RA are already detectable in nave T cells. Nave T cells from RA patients have a lowered signaling threshold of the T cell receptor which may explain why failure in immune tolerance to neoantigens such as citrullinated peptides is the immunological hallmark of RA. They have defects in DNA repair mechanisms which predisposes for increased apoptosis susceptibility and accelerated immunosenescence. And they have rewired their metabolic network shunting glucose preferentially into the pentose phosphate pathway to reduce oxidative stress and produce metabolites necessary for synthetic activities. This application aims at gaining a deeper understanding of T cell dysfunction in RA by characterizing their epigenetic landscape. We will use a recently developed platform, assay for transposase accessible chromatin (ATAC)-sequencing that allows genome-wide mapping of the open chromatin within small populations of isolated T cells including antigen- specific T cells. [Three aims are proposed. The objective of Aim 1 is to identify RA-associated epigenetic signatures in nave T cells by comparing patients with RA, psoriatic arthritis and age-matched controls and relate them to the signatures in memory T cells and autoantigen-specific T cells. Aim 2 will explore the influence of disease activity and treatment on these signatures. By examining transcription factor (TF) target sequences at accessible sites, we will define transcription factor networks that are associated with RA and/or related to cytokine exposure in peripheral blood or the synovial tissue. In Aim 3, we will explore the functional consequences of differential chromatin accessibility by comparing open sites to the transcriptome of T cell subsets before and after activation. In addition, we will determine the relationship of open sites to eQTLs and to causal SNPs implicated in RA. These studies will provide a comprehensive map of promoter and enhancer accessibilities in RA T cells that may determine the transcriptome at resting stage as well as their ability to respond and develop into autoantigen-specific effector T cells.]